+Model

JDMV-744; No. of Pages 7 ARTICLE IN PRESS

JMV—Journal de Médecine Vasculaire (2020) xxx, xxx—xxx

Available online at

ScienceDirect
www.sciencedirect.com

REVIEW

Association between D-Dimer levels and

mortality in patients with coronavirus
disease 2019 (COVID-19): a systematic
review and pooled analysis
M. Sakka a, J.M. Connors b,c, G. Hékimian d, I. Martin-Toutain e,
B. Crichi f, I. Colmegna g, D. Bonnefont-Rousselot a,h,
D. Farge f,g,i,1, C. Frere e,j,1,∗

a
Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Metabolic Biochemistry,
75013 Paris, France
b
Hematology Division, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Boston, MA, USA
c
Harvard Medical School, Boston, MA, USA
d
Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Intensive Care Unit, 75013 Paris, France
e
Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Hematology, 75013
Paris, France
f
Assistance Publique Hôpitaux de Paris, Saint-Louis Hospital, Department of Internal Medicine,
Autoimmune and Vascular Disease Unit, 75010 Paris, France
g
McGill University, Department of Medicine, Montreal, Québec, Canada
h
Paris University, UTCBS, INSERM U1267, CNRS UMR 8258, 75006 Paris, France
i
Paris University, EA 3518, University Institute of Hematology, 75010 Paris, France
j
Sorbonne University, INSERM UMRS 1166, Institute of Cardiometabolism And Nutrition, 75013 Paris, France

Received 3 May 2020; accepted 18 May 2020

KEYWORDS Abstract
Coronavirus disease Background. — Several observational studies have reported elevated baseline D-dimer levels
2019; in patients hospitalized for moderate to severe coronavirus disease 2019 (COVID-19). These
SARS-CoV-2; elevated baseline D-dimer levels have been associated with disease severity and mortality in
D-Dimer; retrospective cohorts.
biomarker; Objectives. — To review current available data on the association between D-Dimer levels and
Mortality mortality in patients admitted to hospital for COVID-19.

∗ Corresponding author at: Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Hematology, 47-83, boulevard

de l’Hôpital, Paris 75013, France

E-mail address: corinne.frere@aphp.fr (C. Frere).
1 Equal contribution.

https://doi.org/10.1016/j.jdmv.2020.05.003
2542-4513/© 2020 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Sakka M, et al. Association between D-Dimer levels and mortality in patients with
coronavirus disease 2019 (COVID-19): a systematic review and pooled analysis. JMV—Journal de Médecine Vasculaire
(2020), https://doi.org/10.1016/j.jdmv.2020.05.003
+Model
JDMV-744; No. of Pages 7 ARTICLE IN PRESS
2 M. Sakka et al.

Methods. — We performed a systematic review of published studies using MEDLINE and EMBASE
through 13 April 2020. Two authors independently screened all records and extracted the out-
comes. A random effects model was used to estimate the standardized mean difference (SMD)
with 95% confidence intervals (CI).
Results. — Six original studies enrolling 1355 hospitalized patients with moderate to critical
COVID-19 (391 in the non-survivor group and 964 in the survivor group) were considered for
the final pooled analysis. When pooling together the results of these studies, D-Dimer levels
were found to be higher in non-survivors than in-survivors. The SMD in D-Dimer levels between
non-survivors and survivors was 3.59 ␮g/L (95% CI 2.79—4.40 ␮g/L), and the Z-score for overall
effect was 8.74 (P < 0.00001), with a high heterogeneity across studies (I2 = 95%).
Conclusions. — Despite high heterogeneity across included studies, the present pooled analysis
indicates that D-Dimer levels are significantly associated with the risk of mortality in COVID-
19 patients. Early integration of D-Dimer testing, which is a rapid, inexpensive, and easily
accessible biological test, can be useful to better risk stratification and management of COVID-
19 patients.
© 2020 Elsevier Masson SAS. All rights reserved.

Introduction D-dimer testing is rapid, reproducible, inexpensive, and eas-

A cluster of pneumonia cases of unknown origin was first
reported in December 2019 in the city of Wuhan, Hubei,
China. This disease, now named coronavirus disease 2019
(COVID-19), rapidly spreads from Wuhan to all countries
around the world. On 30 January 2020, the outbreak of
COVID-19 was declared as a Public Health Emergency of
International Concern by the WHO, then as a global pan-
demic on 12 March 2020. Up to 18 April 2020, there were
2,313,897 confirmed cases of COVID-19 and 159,033 COVID-
19-related deaths worldwide.
Huang et al. first reported the clinical features and out-
comes of 41 COVID-19 patients admitted to a single Wuhan
hospital [1]. Subsequently, several retrospective cohorts
analyzed the clinical characteristic and the course of COVID-
19 in patients suffering from mild to critical forms [2—8].
While most of COVID-19 patients suffer from mild to moder-
ate symptoms and do not require hospitalization, 15—20% of
patients progress to severe pneumonia resulting in hypoxia
and respiratory failure which necessitate supportive care
for critical illness and supplemental nasal oxygen, and 5%
of them progress to acute respiratory distress syndrome
(ARDS) or multiple organ failure (MOF) requiring admittance
to an intensive care unit (ICU) with mechanical ventilation
or extracorporeal membrane oxygenation (ECMO) [9].
Risk factors for developing ARDS and MOF throughout the
course of COVID-19 are not fully understood yet. Due to their
limited capacity, health care systems are facing an unprece-
dented critical crisis worldwide. Early optimized care may
improve prognosis in patients at high risk for developing
the most severe forms, however early identification of poor
prognosis and risk stratification remains challenging. There-
fore, reliable biomarkers or risk assessment models allowing
to earlier predict poor prognosis are warranted to help physi-
cians in decision making regarding the most appropriate
therapeutic approach to further provide the best possible
care for each individual patient.
D-dimers are degradation products of cross-linked fibrin
produced when plasmin cleaves fibrin to break down clots.
ily accessible. Early retrospective cohort studies of COVID-19
patients admitted to hospital reported increased baseline
D-dimer levels in 36% to 43.6% of cases, [1—4] particularly
in patients admitted to ICU. In a recent pooled analysis
of 4 studies including 553 patients, baseline D-Dimer lev-
els were associated with COVID-19 severity [10]. While a
retrospective cohort of 183 severe COVID-19 patients sug-
gested that in the most severe cases high D-dimer levels
could be related to disseminated intravascular coagulation
(DIC) [11], two recent prospective studies aiming to char-
acterize the coagulation profile of COVID-19 ARDS patients
with standard and viscoelastic coagulation tests reported a
pro-coagulant profile without evidence of DIC [12,13].
In the present study, we reviewed all current available
data on the association between D-Dimer levels and mortal-
ity in COVID-19 patients in order to assess the potential of
D-dimer testing for predicting outcomes in patients admit-
ted to hospital.
Methods
We performed a comprehensive literature search of pub-
lished studies from all languages using MEDLINE and EMBASE
through 13 April 2020. The following keywords (MeSH terms)
were used: ‘D-Dimer’ AND (‘Coronavirus disease 2019’ OR
‘COVID-19’ OR ‘SARS-CoV-2’ OR ‘novel corona’ OR ‘2019-
ncov’). We also screened pre-print articles from arXiv.
Studies were eligible to be included in the meta-analysis
if they met the following inclusion criteria:
• original cohort study;
• written in English language;
• reporting separately D-Dimers levels in hospitalized
COVID-19 patients with fatal outcome and in those with-
out fatal outcome.
No restriction was made on the patient disease severity
(i.e. COVID-19 patients with moderate, severe or critical dis-

Please cite this article in press as: Sakka M, et al. Association between D-Dimer levels and mortality in patients with
coronavirus disease 2019 (COVID-19): a systematic review and pooled analysis. JMV—Journal de Médecine Vasculaire
(2020), https://doi.org/10.1016/j.jdmv.2020.05.003
+Model
JDMV-744; No. of Pages 7 ARTICLE IN PRESS
D-Dimers and mortality in COVID-19 patients: a meta-analysis
ease). Comments, letters to the editor, editorial, reviews,
case reports and basic science studies were excluded.
Two authors (M.S. and C.F.) independently screened all
records identified through database searching for study eligi-
bility based on title and abstracts. The agreement between
the reviewers for study selection was assessed using the
kappa statistic [14]. Any discrepancies were resolved by
consensus after discussion between the two authors or upon
consensus from a third author (D.F.). The Newcastle—Ottawa
scale was used to assess the studies quality and risk of bias
[15].
Data were independently extracted by two authors
[including first author’s last name, publication year, study
design, country, study population, study period, sample size,
sex, age, mortality rate, and means and standard devia-
tions (SD) of D-Dimer in COVID-19 hospitalized patients with
fatal outcome and in those without fatal outcome] using a
standardized data extraction form.
Continuous data were represented by mean, SD and
standardized mean difference (SMD) with 95% confidence
intervals (CI). For studies reporting medians and interquar-
tile ranges (IQR), means and SD were estimated according
to the algorithm proposed by Hozo et al. [16] Heterogeneity
among studies was assessed by the I2 statistic, I2 > 50% rep-
resenting high degree of heterogeneity. A random-effects
model was used in order to take into account within-study
and between-study variance. Visualization of funnel plots
was used to assess for publication bias. A P-value < 0.05 was
considered as statistically significant. All statistical analy-
ses were performed using the Cochrane’s Review Manager
software (RevMan, version 5.3, Copenhagen, Denmark).
1. Results
A total of 26 records were identified through database
searching, of which 20 were excluded because they were
editorial (n = 1), review article (n = 1), basic science study
(n = 1), they were written in foreign (Chinese) language
(n = 5), they did not assess mortality as an outcome or
they did not reported D-dimer levels separately in COVID-
19 patients with fatal outcome and in those without fatal
outcome (n = 12).
Finally, 6 original studies enrolling a total of 1355 patients
hospitalized for moderate to critical COVID-19 (391 in the
non-survivor group, and 964 in the survivor group) were con-
sidered for the final pooled analysis. [5—7,11,17,18] The
agreement between authors for study selection was 100%
(kappa statistic 1.0).
The main characteristics of included studies are sum-
marized in Table 1. All studies were retrospective cohorts
conducted in China between December 2019 and February
2020 [5—7,11,17]. The duration of follow-up was unclear
except in one study [6]. All studies were at high risk of bias
according to the Newcastle—Ottawa scale.
The median age of patients ranged from 51 to 62 years.
Most of patients (58.6%) were men. The mortality rate varied
from 11.5 to 29.8% (Table 1). Of note, most studies excluded
patients who were still hospitalized at the end of the study
period (i.e. neither recovered nor died).
Chen et al. [5] compared the baseline clinical and bio-
logical characteristics of 113 hospitalized COVID-19 patients
Please cite this article in press as: Sakka M, et al. Association between D-Dimer levels and mortality in patients with
coronavirus disease 2019 (COVID-19): a systematic review and pooled analysis. JMV—Journal de Médecine Vasculaire
(2020), https://doi.org/10.1016/j.jdmv.2020.05.003
3
who died with those of 161 hospitalized COVID-19 patients
who recovered. D-Dimer levels were higher in non-survivors
(median 4.6 ␮g/mL; IQR 1.3—21.0 ␮g/mL) compared to sur-
vivors (median 0.6 ␮g/mL; IQR 0.3—1.3 ␮g/mL).
Tang et al. (A) [11] compared several coagulation param-
eters, including the values of D-Dimer in 21 hospitalized
COVID-19 patients who died with those of 162 hospital-
ized COVID-19 patients who recovered (n = 78) or were still
hospitalized (n = 84) at time of study. D-dimer values were
significantly higher in non-survivors (median 2.12 ␮g/mL;
IQR: 0.77—5.27 ␮g/mL) compared to survivors (median
0.61 ␮g/mL; IQR: 0.35—1.29 ␮g/mL; P < 0.001).
The same authors [Tang et al. (B)] [17] reported baseline
clinical and biological characteristics of 134 severe hospi-
talized COVID-19 patients who died and those of 315 severe
hospitalized COVID-19 patients still alive at time of the anal-
ysis. D-Dimer levels were significantly higher in non-survivors
(median 4.7 ␮g/mL; IQR 1.42—21.0 ␮g/mL) compared to sur-
vivors (median 1.47 ␮g/mL; IQR 0.78—4.16 ␮g/mL; P < 0.001)
[5]. Multivariate analysis found a significant association
between D-Dimer levels and the 28-days mortality [Odds
ratio (OR) 1.058; 95% CI 1.028—1.090; P < 0.001].
Tu et al. [18] reported clinic-laboratory characteristics
of 25 fatal cases of COVID-19 patients and those of 149
COVID-19 hospitalized patients discharged at time of analy-
sis. D-Dimer levels were significantly higher in non-survivors
(median 3.306 ␮g/mL; IQR 1.79—7.512 ␮g/mL) compared
to survivors (median 0.66 ␮g/mL; IQR 0.37—1.108 ␮g/mL;
P < 0.001).
Wu et al. [6] compared baseline clinical and biological
characteristics of 44 COVID-19 patients with ARDS who died
to those of 40 COVID-19 patients with ARDS who survived
among 201 patients hospitalized for COVID-19. D-Dimer
levels were significantly higher in non-survivors (median
3.95 ␮g/mL; IQR 1.15—10.96 ␮g/mL) compared to survivors
(median 0.49 ␮g/mL; IQR 0.31—1.18 ␮g/mL; P = 0.001).
Finally, Zhou et al. [7] investigated baseline clinical
and biological characteristics of 54 hospitalized patients
with COVID-19 who died and 137 hospitalized patients
with COVID-19 who survived. D-dimer values were signifi-
cantly increased in non-survivors (median 5.2 ␮g/mL; IQR:
1.5—21.1 ␮g/mL) than in survivors (median 0.6 ␮g/mL; IQ:
0.3—1.0 ␮g/mL; P < 0.001).
When pooling together the results from these 6
studies, D-Dimer levels were found to be higher in non-
survivors than in-survivors. The SMD in D-Dimer levels
between non-survivors and survivors was 3.59 ␮g/L (95% CI
2.79—4.40 ␮g/L) (Fig. 1), and the Z-score for overall effect
was 8.74 (P < 0.00001), with a high heterogeneity across
studies (I2 = 95%).
2. Discussion
Retrospective cohorts early reported increased baseline
D-dimer levels in one third of overall COVID-19 patients
admitted to hospital [1—4]. In two studies, significantly
higher levels of D-Dimers were observed in small samples of
patients with severe disease (i.e. admitted to ICU) compared
to those with mild or moderate disease (i.e. not requiring
an admission to ICU) [1,4. A pooled analysis of 4 studies (553
 4

JDMV-744; No. of Pages 7

+Model
(2020), https://doi.org/10.1016/j.jdmv.2020.05.003
coronavirus disease 2019 (COVID-19): a systematic review and pooled analysis. JMV—Journal de Médecine Vasculaire
Please cite this article in press as: Sakka M, et al. Association between D-Dimer levels and mortality in patients with

Table 1 Characteristic of the studies included in the metanalysis.

Reference Year Study design Country Study population Study period Patients, n Male, n (%) Age, median Mortality
(IQR) or mean, rate (%)
years

Chen et al. [5] 2020 Retrospective China Moderately to January 31, 274 (113 171 (62) 62 (44—70) 14.1
case series severely ill or 2020—February non-survivors
critically ill 12, 2020 and 161
patients with survivors)
confirmed
COVID-19
Tang et al. (A) 2020 Retrospective, China Consecutive January 1, 183 (21 98 (53.5) 54.1 ± 16.2 11.5
[11] single-center patients with 2020—February non-survivors

ARTICLE IN PRESS
cohort study confirmed 13, 2020 and 162
COVID-19 survivors)
admitted in a
single center
Tang et al. (B) 2020 Retrospective, China Consecutive January 1, 449 (134 268 (59.6) 65.1 ± 12 29.8
[17] single-center patients with 2020—February non-survivors
cohort study confirmed severe 13, 2020 and 315
COVID-19 survivors
admitted in a
single center
Tu et al. [18] 2020 Retrospective, China Consecutive January 3, 174 (25 79 (45.5) NR 14.4
single-center patients with 2020—February non-survivors
cohort study confirmed severe 24, 2020 and 149
COVID-19 survivors
admitted in a
single center
Wu et al. [6] 2020 Retrospective, China Consecutive December 25, 201 including 128 (63.7) 51 (43—60) 21.9
single-center patients with 2019—Januray 84 patients
cohort study confirmed 26, 2020 with ADRS: 44
COVID-19 Follow-up until non-survivors
admitted in a February 13, and 40
single center 2020 survivors)
Zhou et al. [7] 2020 Retrospective, China Consecutive December 29, 191 (54 119 (62) 56 (46—67) 28.2
multicenter patients with 2019—Januray non-survivors
cohort study confirmed 31, 2020 and 137
COVID-19 survivors)

M. Sakka et al.
admitted in 2
centers
ADRS: acute detress respiratory syndrom; COVID-19: Coronavirus Disease 2019; IQR: interquartile range; NR: not reported.
+Model
JDMV-744; No. of Pages 7 ARTICLE IN PRESS
D-Dimers and mortality in COVID-19 patients: a meta-analysis
Figure 1 Forest plot of Standard Mean Difference of D-Dimer levels between non-survivors and survivors in the 6 included studies
(random effect). Abbreviations: SD: standard deviation; St: Standard; CI: confidence interval.
patients) found an association between D-Dimer levels and
the severity of COVID-19 disease [10].
Our pooled analysis now indicates that D-Dimer lev-
els might be a useful marker for predicting mortality in
COVID-19 patients admitted to hospital and suggests that D-
Dimer testing on admission might be useful to early stratify
patients with COVID-19 admitted to hospital and to further
individualize treatment. However, it was not performed on
individual patient data and the impact of potential con-
founders remains unknown.
Interestingly, Zhou et al. investigated numerous potential
risk factors for in hospital-mortality in 191 patients hospi-
talized for COVID-19. In multivariate analysis, a D-dimer
level >1 ␮g/mL was the best predictor of mortality [Odds
ratio (OR) 18.42, 95% CI 2.64—128.55; P = 0.0033]. [7] Sim-
ilarly, Tang et al. [17] reported that D-Dimer levels were
significantly associated with 28-days mortality (OR 1.058,
95% CI 1.028—1.090; P < 0.001) in a retrospective cohort of
449 patients with severe COVID-19.
To the best of our knowledge, six risk assessment models
(RAM) for predicting mortality among patients with sus-
pected or confirmed COVID-19 have been yet developed.
[19—24] Only three of these RAMs included biological data
(C-reactive protein, lactic dehydrogenase, and lymphocyte
count). However, none of them included D-dimer levels as a
predictor.
More recently, a retrospective study investigated the
prognosis and the optimal cut-off values for baseline D-
dimer levels to predict mortality in 343 COVID-19 patients.
Thirteen deaths occurred during hospitalization. A D-dimer
value ≥ 2.0 ␮g/mL at admission was found to be significan-
tly associated with mortality (Hazard ratio 51.5, 95% CI
12.9—206.7). This cutoff value of 2.0 ␮g/mL predicts mor-
tality with a C-index of 0.89, a sensitivity of 92.3% and a
specificity of 83.3%. [25]
The mechanisms underlying the increase in D-Dimer in
COVID-19 patients is not fully understood. In their retrospec-
tive cohort, Tang et al. found that 71.6% of non-survivors
fulfilled the criteria for sepsis-induced coagulopathy (SIC)
compared to 0.6% in survivors. [11] However, 2 recent
prospective studies reported a pro-coagulant profile in
COVID-19 ARDS patients using standard and viscoelastic
coagulation tests without further evidence of DIC, [12,13]
indicating that the increase in D-Dimers levels, which is
constantly observed in severe COVID-19 cases, might not
be related to DIC. Moreover, in a prospective cohort of 184
patients admitted to ICU for COVID-19 pneumonia, none of
the patients developed DIC. [26]
Please cite this article in press as: Sakka M, et al. Association between D-Dimer levels and mortality in patients with
coronavirus disease 2019 (COVID-19): a systematic review and pooled analysis. JMV—Journal de Médecine Vasculaire
(2020), https://doi.org/10.1016/j.jdmv.2020.05.003
5
In the most severe cases of COVID-19, severe acute respi-
ratory syndrome coronavirus 2 (SARS-CoV-2) infection results
in uncontrolled inflammatory innate and impaired adap-
tive immune responses, as reflected by increased serum
levels of pro-inflammatory cytokines such as IL-6, IL-1␤, IL-
2, IL-8, IL-17, G-CSF, GM-CSF, IP10, MCP1, MIP1␣ and TNF
[27]. Importantly, there is a crosstalk between inflammation
and blood coagulation, the production of pro-inflammatory
cytokines such as TNF-␣, IL-1␤ and IL-6, leading to the upreg-
ulation of tissue factor (TF) expression on the endothelial
cells and monocytes surfaces, further resulting in a procoag-
ulant activity [28]. In addition, autopsy reports of COVID-19
patients found extensive neutrophil infiltration in pulmonary
capillaries, with acute capillaritis and fibrin deposition,
indicating that neutrophil extracellular traps (NETs) may
contribute to organ damage and promote thrombosis [29].
Hypoxia has also been demonstrated to trigger a procoagu-
lant activity through the upregulation of hypoxia-inducible
transcription factors that modulate the expression of sev-
eral coagulation and fibrinolysis factors such as tissue factor
pathway inhibitor, TF, and PAI-1 [30]. Accordingly, there is
mounting evidence that COVID-19 is associated with a pro-
thrombotic state [12,13] resulting in an increased risk of
venous thromboembolism (VTE). Increased D-Dimer levels
might simply reflect this prothrombotic state. Several case
reports have documented an association between COVID-19
and the occurrence of pulmonary embolisms (PE) or in situ
microvascular thrombosis [31—33]. In a chinese retrospec-
tive study of 81 severe COVID-19 patients admitted to ICU
who were not under thromboprophylaxis, the prevalence of
VTE reached 25% [34]. More recently, a prospective cohort of
184 patients admitted to ICU for COVID-19 reported a cumu-
lative incidence of VTE of 27%, PE being the most frequent
event [26]. Therefore, thromboprophylaxis is required in all
hospitalized COVID-19 patients. A call for awareness regard-
ing the need of adapted thromboprophylaxis in COVID-19
patients has been recently published [35].
Potential limitations of the present study should be
acknowledged. First, our analysis included only observa-
tional retrospective studies conducted in a single country,
which may have resulted in biases inherent to such stud-
ies. Selected studies were heterogeneous in terms of study
design, study population, outcome definitions, and length of
follow-up. Second, we converted non-normally distributed
statistics (i.e. median and range) to normally distributed
statistics (i.e. mean and SD), which may also have intro-
duced some bias in the results. Finally, the amount of
included studies and their sample size were limited.
+Model
JDMV-744; No. of Pages 7 ARTICLE IN PRESS
6 M. Sakka et al.
In conclusion, evidence has emerged that D-Dimer test-
ing in combination with clinical factors or other biomarkers
might be useful to early stratify patients with COVID-19
admitted to hospital and to further individualize treatment.
However, it seems premature to use D-Dimer alone to guide
clinical decision-making. Further large prospective studies
to validate the prognosis performances of D-Dimer and to
determine the best cutoff value to be used are warranted.
Author contributions
M. Sakka, J.M. Connors, D. Farge and C. Frere designed the
study and collected the data. C. Frere performed the sta-
tistical analysis. M. Sakka, J.M. Connors, D. Farge and C.
Frere drafted and revised the manuscript. Other authors
contributed to critical of intellectual content, and final
approval.
Disclosure of interest
The authors declare that they have no competing interest.
References
[1] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical
features of patients infected with 2019 novel coronavirus in
Wuhan, China. Lancet 2020;395:497—506.
[2] Guan W-J, Ni Z-Y, Hu Y, Liang W-H, Ou C-Q, He J-X, et al. Clinical
Characteristics of Coronavirus Disease 2019 in China. N Engl J
Med 2020;382:1708—20.
[3] Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemi-
ological and clinical characteristics of 99 cases of 2019 novel
coronavirus pneumonia in Wuhan, China: a descriptive study.
Lancet 2020;395:507—13.
[4] Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical
characteristics of 138 hospitalized patients with 2019 novel
coronavirus-infected pneumonia in Wuhan, China. JAMA 2020,
http://dx.doi.org/10.1001/jama.2020.1585.
[5] Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clini-
cal characteristics of 113 deceased patients with coronavirus
disease 2019: retrospective study. BMJ 2020:368, m1091.
[6] Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al.
Risk factors associated with acute respiratory distress syn-
drome and death in patients with Coronavirus disease
2019 pneumonia in Wuhan, China. JAMA Intern Med 2020,
http://dx.doi.org/10.1001/jamainternmed.2020.0994.
[7] Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course
and risk factors for mortality of adult inpatients with COVID-
19 in Wuhan, China: a retrospective cohort study. Lancet
2020;395:1054—62.
[8] Zhou Y, Zhang Z, Tian J, Xiong S. Risk factors associated with
disease progression in a cohort of patients infected with the
2019 novel coronavirus. Ann Palliat Med 2020;9:428—36.
[9] Wu Z, McGoogan JM. Characteristics of and important lessons
from the Coronavirus Disease 2019 (COVID-19) Outbreak in
China: summary of a report of 72314 cases from the chi-
nese center for disease control and prevention. JAMA 2020,
http://dx.doi.org/10.1001/jama.2020.2648.
[10] Lippi G, Favaloro EJ. D-dimer is associated with severity of
Coronavirus Disease 2019: a pooled analysis. Thromb Haemost
2020;120:876—8.
[11] Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parame-
ters are associated with poor prognosis in patients with novel
coronavirus pneumonia. J Thromb Haemost 2020;18:844—7.
Please cite this article in press as: Sakka M, et al. Association between D-Dimer levels and mortality in patients with
coronavirus disease 2019 (COVID-19): a systematic review and pooled analysis. JMV—Journal de Médecine Vasculaire
(2020), https://doi.org/10.1016/j.jdmv.2020.05.003
[12] Ranucci M, Ballotta A, Di Dedda U, Bayshnikova E, Dei Poli
M, Resta M, et al. The procoagulant pattern of patients
with COVID-19 acute respiratory distress syndrome. J Thromb
Haemost 2020, http://dx.doi.org/10.1111/jth.14854.
[13] Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C,
Chantarangkul V, et al. Hypercoagulability of COVID-19 patients
in Intensive Care Unit. A report of thromboelastography find-
ings and other parameters of hemostasis. J Thromb Haemost
2020, http://dx.doi.org/10.1111/jth.14850.
[14] McGinn T, Wyer PC, Newman TB, Keitz S, Leipzig R. For GG,
Evidence-Based Medicine Teaching Tips Working group. Tips for
learners of evidence-based medicine: 3. Measures of observer
variability (kappa statistic). CMAJ 2004;171:1369—73.
[15] Wells G, Shea B, O’Connell D, Peterson J, Welch V,
Losos M, et al. The Newcastle-Ottawa Scale (NOS) for
assessing the quality of nonrandomized studies in meta-
analyses. Ottawa Health Research Institute; 2011. Available at:
www.ohri.ca/programs/clinical epidemiology/oxford.asp.
[16] Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and vari-
ance from the median, range, and the size of a sample. BMC
Med Res Methodol 2005;5:13.
[17] Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant
treatment is associated with decreased mortality in severe
coronavirus disease 2019 patients with coagulopathy. J Thromb
Haemost 2020;18:1094—9.
[18] Tu W-J, Cao J, Yu L, Hu X, Liu Q. Clinicolaboratory study of
25 fatal cases of COVID-19 in Wuhan. Intensive Care Med 2020,
http://dx.doi.org/10.1007/s00134-020-06023-4.
[19] Xie J, Hungerford D, Chen H, Abrams ST, Li S, Wang G, et al.
Development and external validation of a prognostic multi-
variable model on admission for hospitalized patients with
COVID-19. medRxiv Cold Spring Harbor Laboratory Press; 2020,
2020.03.28.20045997.
[20] Caramelo F, Ferreira N, Oliveiros B. Estimation of risk fac-
tors for COVID-19 mortality - preliminary results. medRxiv Cold
Spring Harbor Laboratory Press; 2020, 2020.02.24.20027268.
[21] Lu J, Hu S, Fan R, Liu Z, Yin X, Wang Q, et al. ACP risk
grade: a simple mortality index for patients with confirmed
or suspected severe acute respiratory syndrome coronavirus
2 disease (COVID-19) during the early stage of outbreak in
Wuhan, China. medRxiv Cold Spring Harbor Laboratory Press;
2020, 2020.02.20.20025510.
[22] Yan L, Zhang H-T, Goncalves J, Xiao Y, Wang M, Guo Y, et al.
A machine learning-based model for survival prediction in
patients with severe COVID-19 infection. medRxiv Cold Spring
Harbor Laboratory Press; 2020, 2020.02.27.20028027.
[23] Yuan M, Yin W, Tao Z, Tan W, Hu Y. Association of radiologic
findings with mortality of patients infected with 2019 novel
coronavirus in Wuhan, China. PLoS ONE 2020;15:e0230548.
[24] Shi Y, Yu X, Zhao H, Wang H, Zhao R, Sheng J. Host suscep-
tibility to severe COVID-19 and establishment of a host risk
score: findings of 487 cases outside Wuhan. Crit Care 2020;
24:108.
[25] Zhang L, Yan X, Fan Q, Liu H, Liu X, Liu Z, et al. D-dimer lev-
els on admission to predict in-hospital mortality in patients
with Covid-19. J Thromb Haemost 2020, http://dx.doi.org/
10.1111/jth.14859.
[26] Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers
DAMPJ, Kant KM, et al. Incidence of thrombotic complications
in critically ill ICU patients with COVID-19. Thromb Res
2020, http://dx.doi.org/10.1016/j.thromres.2020.04.013, pii:
S0049-3848(20)30120-1.
[27] Cao X. COVID-19: immunopathology and its implications for
therapy. Nat Rev Immunol 2020;20:269—70.
[28] Okamoto T, Suzuki K. The Role of Gap Junction-Mediated
Endothelial Cell—Cell Interaction in the Crosstalk between
Inflammation and Blood Coagulation. Int J Mol Sci 2017:18,
http://dx.doi.org/10.3390/ijms18112254, pii: E2254.
+Model
JDMV-744; No. of Pages 7 ARTICLE IN PRESS
D-Dimers and mortality in COVID-19 patients: a meta-analysis 7

[29] Barnes BJ, Adrover JM, Baxter-Stoltzfus A, Borczuk A, Cools-
Lartigue J, Crawford JM, et al. Targeting potential drivers of
COVID-19: Neutrophil extracellular traps. J Exp Med 2020:217,
http://dx.doi.org/10.1084/jem.20200652, pii: e20200652.
[30] Gupta N, Zhao Y-Y, Evans CE. The stimulation of thrombosis by
hypoxia. Thromb Res 2019;181:77—83.
[31] Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary
embolism COVID-19 pneumonia: a random association? Eur
Heart J 2020;41:1858.
[32] Xie Y, Wang X, Yang P, Zhang S. COVID-19 Complicated by Acute
Pulmonary Embolism. Radiology 2020;2:e200067.
[33] Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al.
Coagulopathy and Antiphospholipid Antibodies in Patients with
Covid-19. N Engl J Med 2020;382:e38.
[34] Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous throm-
boembolism in patients with severe novel coronavirus pneu-
monia. J Thromb Haemost 2020, http://dx.doi.org/10.101111/
jth14830.
[35] Wang T, Chen R, Liu C, Liang W, Guan W, Tang R, et al. Attention
should be paid to venous thromboembolism prophylaxis in the
management of COVID-19. Lancet Haematol 2020;7:e362—3.

Please cite this article in press as: Sakka M, et al. Association between D-Dimer levels and mortality in patients with
coronavirus disease 2019 (COVID-19): a systematic review and pooled analysis. JMV—Journal de Médecine Vasculaire
(2020), https://doi.org/10.1016/j.jdmv.2020.05.003